Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models.
Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models.
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DOI：
10.1016/j.tranon.2018.05.004
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发表时间：
2018-08
影响因子：
5
通讯作者：
Baruchel S
中科院分区：
文献类型：
--
作者：
Kumar S;Sun JD;Zhang L;Mokhtari RB;Wu B;Meng F;Liu Q;Bhupathi D;Wang Y;Yeger H;Hart C;Baruchel S
抗血管生成治疗在临床前和临床试验中显示出有希望的结果。然而，肿瘤细胞通过获得在抗血管生成治疗诱导的缺氧下存活和增殖的能力而获得对这种治疗的抗性。将抗血管生成治疗与缺氧激活的前药相结合可以克服这一局限性。在这里，我们测试了抗血管生成药物舒尼替尼与缺氧激活的前药evofosfamide在神经母细胞瘤中的组合。在体外，神经母细胞瘤细胞系SK-N-BE（2）在缺氧条件下对evofosfamide的敏感性是常氧条件下的40倍。在IV转移模型中，与溶媒相比，evofosfamide显著增加小鼠存活率（P=.02）。在SK-N-BE（2）皮下异种移植模型中，我们使用30 mg/kg舒尼替尼和50 mg/kg evofosfamide测试了两种不同的治疗方案。在皮下SK-N-BE（2）异种移植模型中，舒尼替尼治疗在沿着evofosfamide治疗时显示出比单药治疗更高的疗效，而舒尼替尼在evofosfamide治疗后7天开始治疗时与任一单药治疗相比没有任何优势。肿瘤切片的免疫荧光显示，当两种治疗一起开始时，与任一单一药物相比，凋亡细胞和缺氧区域的数量更高。在异种移植和转移模型中，80 mg/kg舒尼替尼与50 mg/kg evofosfamide的治疗显著上级单一药物。本研究证实了舒尼替尼和evofosfamide在侵袭性神经母细胞瘤小鼠模型中的临床前疗效。舒尼替尼通过增加缺氧区域增强evofosfamide的疗效，evofosfamide靶向缺氧肿瘤细胞。因此，每种药物都会增强另一种药物的活性。
Antiangiogenic therapy has shown promising results in preclinical and clinical trials. However, tumor cells acquire resistance to this therapy by gaining ability to survive and proliferate under hypoxia induced by antiangiogenic therapy. Combining antiangiogenic therapy with hypoxia-activated prodrugs can overcome this limitation. Here, we have tested the combination of antiangiogenic drug sunitinib in combination with hypoxia-activated prodrug evofosfamide in neuroblastoma. In vitro, neuroblastoma cell line SK-N-BE(2) was 40-folds sensitive to evofosfamide under hypoxia compared to normoxia. In IV metastatic model, evofosfamide significantly increased mice survival compared to the vehicle (P=.02). In SK-N-BE(2) subcutaneous xenograft model, we tested two different treatment regimens using 30 mg/kg sunitinib and 50 mg/kg evofosfamide. Here, sunitinib therapy when started along with evofosfamide treatment showed higher efficacy compared to single agents in subcutaneous SK-N-BE(2) xenograft model, whereas sunitinib when started 7 days after evofosfamide treatment did not have any advantage compared to treatment with either single agent. Immunofluorescence of tumor sections revealed higher number of apoptotic cells and hypoxic areas compared to either single agent when both treatments were started together. Treatment with 80 mg/kg sunitinib with 50 mg/kg evofosfamide was significantly superior to single agents in both xenograft and metastatic models. This study confirms the preclinical efficacy of sunitinib and evofosfamide in murine models of aggressive neuroblastoma. Sunitinib enhances the efficacy of evofosfamide by increasing hypoxic areas, and evofosfamide targets hypoxic tumor cells. Consequently, each drug enhances the activity of the other.
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影响因子：
8.8
作者：
Yoon C;Lee HJ;Park DJ;Lee YJ;Tap WD;Eisinger-Mathason TS;Hart CP;Choy E;Simon MC;Yoon SS
通讯作者：
Yoon SS
影响因子：
11.1
作者：
McIntyre A;Harris AL
通讯作者：
Harris AL
影响因子：
3
作者：
Phillips RM
通讯作者：
Phillips RM
影响因子：
3.6
作者：
Sun JD;Liu Q;Ahluwalia D;Li W;Meng F;Wang Y;Bhupathi D;Ruprell AS;Hart CP
通讯作者：
Hart CP
影响因子：
3.7
作者：
Calero, Raul;Morchon, Esther;Serrano, Rosario
通讯作者：
Serrano, Rosario